Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors
A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, th...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-01, Vol.19 (1), p.264-274 |
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| creator | Chirapu, Srinivas Reddy Pachaiyappan, Boobalan Nural, Hikmet F. Cheng, Xin Yuan, Hongbin Lankin, David C. Abdul-Hay, Samer O. Thatcher, Gregory R.J. Shen, Yong Kozikowski, Alan P. Petukhov, Pavel A. |
| description | A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand
5b reduced 65% of Aβ40 production in N2a cells stably transfected with Swedish human APP. |
| doi_str_mv | 10.1016/j.bmcl.2008.10.096 |
| format | Article |
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5b reduced 65% of Aβ40 production in N2a cells stably transfected with Swedish human APP.</description><subject>Alzheimer</subject><subject>Amyloid beta-Peptides - antagonists & inhibitors</subject><subject>Amyloid beta-Peptides - biosynthesis</subject><subject>Amyloid beta-Protein Precursor - genetics</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>Aspartic protease</subject><subject>BACE1</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Computer Simulation</subject><subject>Computer-aided molecular design</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. 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Drug treatments</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. 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5b reduced 65% of Aβ40 production in N2a cells stably transfected with Swedish human APP.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19013792</pmid><doi>10.1016/j.bmcl.2008.10.096</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2009-01, Vol.19 (1), p.264-274 |
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| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Alzheimer Amyloid beta-Peptides - antagonists & inhibitors Amyloid beta-Peptides - biosynthesis Amyloid beta-Protein Precursor - genetics Amyloid Precursor Protein Secretases - antagonists & inhibitors Aspartic Acid Endopeptidases - antagonists & inhibitors Aspartic protease BACE1 Binding Sites Biological and medical sciences Cell Line Computer Simulation Computer-aided molecular design Drug Design Humans Ligands Medical sciences Models, Molecular Neuropharmacology Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - pharmacology Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Transfection |
| title | Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors |
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